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Abstract Background Triple-negative breast cancer (TNBC) is currently the most aggressive subtype of breast cancer, characterized by high heterogeneity and strong invasiveness, and currently lacks effective therapies. PRMT5, a type II protein arginine methyltransferase, is upregulated in numerous cancers, including TNBC, and plays a critical role, marked it as an attractive therapeutic target. PROTAC (Proteolysis Targeting Chimeras) is an innovative drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade target proteins, which is characterized by higher activity, enhanced safety, lower resistance, and reduced toxicity, offering significant value for clinical translation. Methods This study utilizes the PROTAC technology to develop potential degraders targeting PRMT5 in vitro and in vivo. Results Through the design, synthesis and screening of a series of targeted compounds, we identified YZ-836P as an effective compound that exerted cytotoxic effects and reduced the protein levels of PRMT5 and its key downstream target protein KLF5 in TNBC after 48 h. Its efficacy was significantly superior to the PRMT5 PROTAC degraders that had been reported. YZ-836P induced G1 phase cell cycle arrest and significantly induced apoptosis in TNBC cells. Additionally, we demonstrated that YZ-836P promoted the ubiquitination and degradation of PRMT5 in a cereblon (CRBN)-dependent manner. Notably, YZ-836P exhibited pronounced efficacy in inhibiting the growth of TNBC patient-derived organoids and xenografts in nude mice. Conclusions These findings position YZ-836P as a promising candidate for advancing treatment modalities for TNBC. Trial registration Ethics Committee of Yunnan Cancer Hospital, KYCS2023-078. Registered 7 June 2023.

Abstract Background There is no optimal reconstruction technique after proximal gastrectomy. The esophagogastrostomy (EG) is a rather simple procedure technically, but the incidences of reflux esophagitis and anastomotic stricture are higher. While the double-tract reconstruction (DTR) can lessen postoperative reflux esophagitis, it is technically complex with a long operation time. The purpose of this study was to evaluate the quality of life (QoL) and short-term outcomes of the two reconstruction techniques. Methods We retrospectively collected consecutive patients with upper-third gastric adenocarcinoma and adenocarcinoma of the esophagogastric junction (AEG) at our center between 2019 June and 2023 May. Patients who underwent laparoscopic proximal gastrectomy (LPG) with EG or DTR were included in this study. A comparison was made between the clinical and pathological characteristics of patients and their surgical parameters, postoperative complications, and its 1-year QoL in two groups. The QoL of the two groups was assessed by Visick grading, the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-STO22 scales at 1 year after operation. The nutritional status of the two groups was evaluated by BMI, hemoglobin and serum albumin. Results AII the qualified patients were divided EG group (n = 63) and DTR group (n = 93). Compared to the DTR group, the blood loss volume of EG group was more (p = 0.001). There were no significant differences in operation duration, number of lymph nodes dissected, and postoperative length of stay between the two groups(p > 0.05). No statistical differences were observed in terms of the incidence of early complications and Clavien-Dindo classification as well(p > 0.05). After one year, the Visick grade of the DTR group was better than EG group (p = 0.040). The multivariable logistic regression analysis showed the only independent risk factor for reflux esophagitis was the reconstruction method. According to the EORTC QLQ-C30 questionnaire, patients in the DTR group had a better global health status(p = 0.001) and complained less about nausea and vomiting(p = 0.033), and appetite loss (p = 0.022). Patients in the DTR group complained less about reflux (p = 0.030) based on the EORTC QLQ-STO22 questionnaire. The multiple linear regression analysis revealed that the reconstruction method, reflux esophagitis and age had a linear relationship with the global health status score. Regarding nutritional status, BMI of the two groups both decreased 1 year after operation, and BMI decline value of the DTR group was lower than EG group (p = 0.001). There is no statistically significant difference between the two groups as for postoperative change in hemoglobin and serum albumin. Conclusion Our findings suggest that it is possible for skilled surgeons to achieve minimal blood loss volume without significantly increasing operation duration when performing DRT, which does not raise risk. In terms of anti-reflux, postoperative QoL and BMI maintenance, 1-year postoperative follow-up outcomes reveal the DTR is superior to EG, which deserve further research and promotion.

Main objective of this research to eliminate the resonant vibrations and stabilize the unstable motion of a self-excited structure through the implementation of an innovative active control strategy. The control strategy coupling the self-excited structure with a second-order filter, which feedback gain $ \lambda $ and control gain $ \beta $, as well as a first-order filter, which feedback gain $ \delta $ and control gain $ \gamma $. The coupling of the second-order filter to establish an energy bridge between the structure and the filter to pump out the structure's vibration energy to the filter. In contrast, the primary purpose of coupling the first-order filter to stabilize the closed loop by adjusting the damping of the system using the control keys $ \delta $ and $ \gamma $. Accordingly, the mathematical model of the proposed control system formulated, incorporating the closed-loop time delay $ \tau $. An analytical solution for the system model obtained, and a nonlinear algebraic system for the steady-state dynamics of the controlled structure extracted. The system's bifurcation characteristics analyzed in the form of stability charts and response curves. Additionally, the system's full response simulated numerically. Findings the high performance of the introduced controller in eliminating the structure's resonant vibrations and stabilizing non-resonant unstable motion. In addition, analytical and numerical investigations revealed that the frequency band within which the second-order filter can absorb the structure's resonant oscillation relies on the algebraic product of $ \beta $ and $ \lambda $. Furthermore, it was found that the equivalent damping of the system depends on the algebraic product of $ \gamma $ and $ \delta $, which can be employed to stabilize the negatively damped self-excited systems. Finally, it reported that although the loop delay can potentially degrade vibration control performance, the time-delay stability margin is nonlinearly proportional to the product of $ \gamma $ and $ \delta $. This finding that increasing the value of $ \gamma \times \delta $ can compensate for the adverse effects of loop delay on both system stability and vibration suppression efficiency.

Abstract Senecavirus A (SVA), an emerging virus that causes blisters on the nose and hooves, reduces the production performance of pigs. RSAD2 is a radical S-adenosylmethionine (SAM) enzyme, and its expression can suppress various viruses due to its broad antiviral activity. However, the regulatory relationship between SVA and RSAD2 and the mechanism of action remain unclear. Here, we demonstrated that SVA infection increased RSAD2 mRNA levels, whereas RSAD2 expression negatively regulated viral replication, as evidenced by decreased viral VP1 protein expression, viral titres, and infected cell numbers. Viral proteins that interact with RSAD2 were screened, and the interaction between the 2 C protein and RSAD2 was found to be stronger than that between other proteins. Additionally, amino acids (aa) 43–70 of RSAD2 were crucial for interacting with the 2 C protein and played an important role in its anti-SVA activity. RSAD2 was induced by type I interferon (IFN-I) via Janus kinase signal transducer and activator of transcription (JAK-STAT), and had antiviral activity. Ruxolitinib, a JAK-STAT pathway inhibitor, and the knockdown of JAK1 expression substantially reduced RSAD2 expression levels and antiviral activity. Taken together, these results revealed that RSAD2 blocked SVA infection by interacting with the viral 2 C protein and provide a strategy for preventing and controlling SVA infection.

Abstract Causal discovery with prior knowledge is important for improving performance. We consider the incorporation of marginal causal relations, which correspond to the presence or absence of directed paths in a causal model. We propose the Marginal Prior Causal Knowledge PC (MPPC) algorithm to incorporate marginal causal relations into a constraint-based structure learning algorithm. We provide the theorems of conditional independence properties by combining observational data and marginal causal relations. We compare the MPPC algorithm with other structure learning methods in both simulation studies and real-world networks. The results indicate that, compare with other constraint-based structure learning methods, MPPC algorithm can incorporate marginal causal relations and is more effective and more efficient.

Abstract Achieving stable and reliable 2D-2D van der Waals heterostructures remains challenging. The broadest strategy for synthesizing these heterostructures is growth or manually stacking one material on top of the other, yet it is inefficient. Here, we present a strategy for synthesizing covalently bonded MoS2-graphene heterostructures using organic linkers with two anchor sites at a low cost. Our covalent heterostructures exhibit a more homogeneously alternating structure than the corresponding randomly alternating structure of vdW heterostructures, as confirmed by surface-enhanced Raman spectroscopy (SERS) measurements. Moreover, different linkers can be used to adjust the interlayer distance between graphene and MoS2, leading to significant impacts on their optical and electrochemical properties, including Photoluminescence (PL), cyclic voltammetry (CV), Ultraviolet-visible spectroscopy (UV-Vis), and SERS. Our strategy offers opportunities to advance fundamental research and enable the practical application of 2D/2D van der Waals heterostructures in various fields, including optoelectronics, energy storage, and catalysis.

The Tibetan Plateau is characterized by high ozone concentration which poses a significant public health concern. However, the causal evidence linking ozone pollution to adverse cardiopulmonary health impacts, as well as the understanding of its underlying biological mechanisms, remains limited. Additionally, exposure levels to particulate and other gaseous air pollutants along with their associated health effects in this region are largely unknown. To address these gaps, we conducted a prospective follow-up study in Tibet from May 2021 to November 2021. In consideration of the potential synergistic effects of chronic hypobaric hypoxia, two Tibetan cities with different altitudes, Lhasa (3650 m) and Nyingchi (3000 m), were chosen to implement atmospheric monitoring and health measurement. We employed cutting-edge, high-precision instruments at stationary monitoring sites to measure ambient air pollution and collected particle samples. Portable devices were used to monitor personal exposure levels of ozone and black carbon. A total of 212 healthy Tibetan college students participated in up to four clinical visits, yielding 774 visits in total, during which functional endpoints were measured and biological samples were collected. The primary aim of this study is to evaluate the cardiorespiratory effects of ambient ozone under hypoxic conditions, where its impact may be amplified due to the region's unique environmental characteristics. The secondary aim is to provide a comprehensive assessment of other air pollutants, including their exposure levels, sources, and health effects. By addressing these aims, the study offers valuable insights into air quality and its health implications in this unique high-altitude setting. This paper outlines the research motivation, measurement framework, and preliminary findings.

Avian metapneumovirus subgroup C (aMPV/C) is an emerging pathogen that causes acute respiratory infection in chickens and turkeys. Sequestosome 1 (SQSTM1), a selective autophagy receptor, regulates cellular activity or viral replication by recognizing ubiquitinated substrates. Here, we found that SQSTM1 expression inhibits aMPV/C replication through selective autophagy. In particular, SQSTM1 interacts with the aMPV/C M2-2 protein via its PB1 domain, and by recognizing a ubiquitinated lysine at position 67 of viral M2-2 protein. This recognition leads to the autophagic degradation of the aMPV/C M2-2 protein, suppressing viral replication.

Abstract Cognitive impairments, which can be caused by neurodegenerative and cerebrovascular disease, represent a growing global health crisis with far‐reaching implications for individuals, families, healthcare systems, and economies worldwide. Notably, neurodegenerative‐induced cognitive impairment often presents a different pattern and severity compared to cerebrovascular‐induced cognitive impairment. With the development of computational technology, machine learning techniques have developed rapidly, which offers a powerful tool in radiomic analysis, allowing a more comprehensive model that can handle high‐dimensional, multivariate data compared to the traditional approach. Such models allow the prediction of the disease development, as well as accurately classify disease from overlapping symptoms, therefore facilitating clinical decision making. This review will focus on the application of machine learning‐based radiomics on cognitive impairment caused by neurogenerative and cerebrovascular disease. Within the neurodegenerative category, this review primarily focuses on Alzheimer's disease, while also covering other conditions such as Parkinson's disease, Lewy body dementia, and Huntington's disease. In the cerebrovascular category, we concentrate on poststroke cognitive impairment, including ischemic and hemorrhagic stroke, with additional attention given to small vessel disease and moyamoya disease. We also review the specific challenges and limitations when applying machine learning radiomics, and provide our suggestion to overcome those limitations towards the end, and discuss what could be done for future clinical use.

Abstract 2D transition metal dichalcogenide materials have attracted increasing attention as active surface‐enhanced Raman spectroscopy (SERS) platforms. In this study, the influence of n‐ and p‐type doping of exfoliated MoS2 (exMoS2) hybrids on the SERS performance is investigated, employing Rhodamine 6G (R6G) as a probe molecule. It is demonstrated that n‐doped exMoS2 hybrids (exMoS2 mixed with C60, graphene, and sodium dodecyl sulfate) exhibit enhanced SERS intensities, while p‐doping (exMoS2 mixed with TCNQ) resulted in inhibited SERS enhancement. A key discovery is the linear relationship between Raman enhancement of MoS2/dopant hybrids and the difference in their LUMO energy levels, which dictate the degree and direction of charge transfer. Interestingly, MC60‐4, a C60‐doped hybrid, deviates from the linear relationship, displaying remarkable SERS enhancement owing to its chemical interaction and unique Raman scattering activity. The findings provide critical insights into the SERS enhancement behavior of doped MoS2, facilitating precise tuning of SERS intensities by manipulating the MoS2 doping state.

Abstract The permanent magnet eddy‐current coupler (PMEC) is a kind of non‐contact, stepless speed regulation device and has been widely used in transmissions. However, the current PMECs are coaxial and cannot achieve transmission and speed regulation in intersecting axes. An intersecting‐axis permanent magnet (PM) eddy current coupler (IPMEC), which consists of a disk‐type PM rotor and a barrel‐type conductive sheet (CS) rotor arranged with intersecting axes, is proposed. It generates eddy currents through the speed difference between the two rotors and uses the non‐contact electromagnetic force between the eddy currents and permanent magnets to transmit torque. During operation, the speed can be adjusted by altering the coupling area or air gap. A theoretical model of the IPMEC based on the equivalent magnetic circuit method is presented and verified by finite element simulation using ANSYS. Then, the effects of the pole number of the PMs, the radius of the CS rotor and the PM rotor on the performance were analysed, and the design method of the IPMEC was proposed. This study can be used to expand the application range of PMECs.

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disease.However, there are few cases of Charcot Neuro-osteoarthropathy (CN) caused by rheumatoid diseases in clinical reports. It is not easy to pay attention to the diagnosis of CN in the complications of rheumatoid disease, which greatly increases the probability of misdiagnosis and missed diagnosis. This case reported a rare complication of rheumatoid arthritis, Charcot arthritis, and the molecular mechanism and diagnosis and treatment of CN caused by RA were systematically discussed. Case presentation The patient, a 79-year-old woman, was hospitalized due to bilateral shoulder pain, limited activity for half a year, aggravated for 4 months to the hospital. During this period, the symptoms did not improve after treatment with acupuncture and Chinese medicine. The patient was previously diagnosed with rheumatoid arthritis for more than 3 years and intermittent irregular use of methylprednisolone and methotrexate for 2 years. She had a history of osteoporosis. Physical examination: symmetrical malformed swelling of the finger joints of both hands; Bilateral supraspinatus and deltoid muscle atrophy, tenderness at the acromion, and attachment of the long head tendon of the biceps brachii were observed. The left Dugas test and the right Dugas test were positive.Blood test: anti-cyclic citrullinated peptide antibody (A-CCP) 33.10U/ml (normal range: 0-5RU/ml); antinuclear antibody quantification (ANA) 47.40AU/ml (normal range: Negative or

In an active magnetic bearings (AMBs) model, every pair of opposite poles is aligned at an angle with the horizontal axis. In some configurations, there is a pair of poles which is in line with the horizontal axis. In other configurations, the same pair of poles might make a nonzero angle with the horizontal axis. This paper focused on the effect of changing such a configuration angle on the control process of an oscillatory rotor in an 8-pole active magnetic bearings model. Adopting the proportional-derivative (PD) control algorithm, the radial or Cartesian control techniques were applied. It was found that the rotor's oscillation amplitudes were not affected by the change in the configuration angle, even if its rotation speed and eccentricity were varied in the radial control scheme. However, the amplitudes were severely affected by the change in the configuration angle except at a specific angle in the Cartesian control scheme. The approximate modulating amplitudes and phases of the rotor's oscillations were extracted by the method of multiple-scales and a stability condition was tested based on the eigenvalues of the corresponding Jacobian matrix.

Endosulfan and hexachlorobenzene (HCB) were previously widely used organochlorine pesticides. Much attention has been paid to trends in human exposure to endosulfan and HCB and to the transport and distribution of endosulfan and HCB within the body. We determined endosulfan I, endosulfan II, and HCB concentrations in serum samples collected from the general population of Wuxi in Jiangsu Province (China) between 2012 and 2016. The endosulfan concentrations varied little throughout the study period, but the HCB concentrations increased. The HCB concentrations were significantly higher in serum from overweight people and smokers than in serum from normal weight people (p = 0.028) and non-smokers (p = 0.011), respectively. HCB binds to human serum albumin (HSA) and can form halogen bonds to CYS-461 and ARG-484 at site II (subdomain IIIA). Fatty acids and nicotine increase the affinity between HCB and HSA, explaining the higher HCB concentrations in serum from overweight people and smokers than normal weight people and non-smokers, respectively.

The debate over whether light’s momentum within a medium is accurately described by Abraham or Minkowski formulation has persisted for over a century. To our knowledge, this dilemma has not been explored within the context of Smith–Purcell radiation. This is because, in conventional Smith–Purcell radiation scenarios, the refractive index is equal to one, leading both the Abraham and Minkowski formulations to yield identical results. Here, we investigate the Abraham–Minkowski dilemma within the realm of Smith–Purcell radiation from photonic crystals, where the refractive index deviates from one. In particular, we find that 3 MeV free electrons impinge a photonic crystal with a grating length of 2.1 μm, resulting in the emission of red light when analyzed based on Abraham’s momentum and blue light when analyzed based on Minkowski’s momentum. In addition, our findings reveal that the disparity in wavelength as predicted by Abraham’s momentum and Minkowski’s momentum depends on the grating length and the refractive index. Our findings offer a method to address the Abraham–Minkowski dilemma within the context of Smith–Purcell radiation, thereby enhancing our understanding of both the Abraham–Minkowski dilemma and Smith–Purcell radiation.

Abstract Designing and making sustainable plastics is especially urgent to reduce their ecological and environmental impacts. However, it remains challenging to construct plastics with simultaneous high sustainability and outstanding comprehensive performance. Here, a composite strategy of in situ polymerizing a petroleum‐based monomer with the presence of an industrialized bio‐derived polymer in a quasi‐solvent‐free system is introduced, affording the plastic with excellent mechanical robustness, impressive thermal and solvent stability, as well as low energy, consumes during production, processing, and recycling. Particularly, the plastic can be easily processed into diverse shapes through 3D printing, injection molding, etc. during polymerization and further reprocessed into other complex structures via eco‐friendly hydrosetting. In addition, the plastic is mechanically robust with Young's modulus of up to 3.7 GPa and tensile breaking strength of up to 150.2 MPa, superior to many commercially available plastics and other sustainable plastics. It is revealed that hierarchical hydrogen bonds in plastic predominate the well‐balanced sustainability and performance. This work provides a new path for fabricating high‐performance sustainable plastic toward practical applications, contributing to the circular economy.

With the introduction of China’s “Carbon Peaking Action Plan Before 2030,” the transformation of the power industry has released huge opportunities and potential. The DC distribution network can well-coordinate the contradiction between distributed power and grid access, fully develop the benefits of distributed energy, and become a new direction for the development of the power industry. However, the current traditional DC–DC converters have problems such as single-topology structure and low power density, which can only complete one-way transmission of energy; hence, the distributed energy cannot be fully utilized. Addressing the problem of distributed energy transfer, this paper is based on a three-port DC–DC converter for a low-voltage DC distribution network to realize energy transfer between the DC distribution network, distributed energy, and low-voltage load. First, the energy transfer modes of the three-port DC–DC converter are introduced. Combined with the converter topology and energy transfer mode, a simplified equivalent model of the converter is established. The voltage gain characteristics and frequency characteristics of this converter are studied. Furthermore, the effects of the excitation inductance to primary resonance inductance ratio parameter k and quality factor Q on the voltage gain characteristics of the converter are discussed. On this basis, the resonant cavity design of the converter is based on the optimal selection of parameters k and Q so that the converter can meet the voltage gain requirements in both forward and reverse operations. The simulation results under different loads verify the reasonableness of the resonant cavity component selection.

IntroductionSince their identification in 1974, circoviruses have caused clinicopathological diseases in various animal species, including humans. However, their origin, transmission, and genetic evolution remain poorly understood.MethodsIn this study, the genome sequences of circovirus were obtained from GenBank, and the Bayesian stochastic search variable selection algorithm was employed to analyzed the evolution and origin of circovirus.ResultsHere, the evolutionary origin, mode of transmission, and genetic recombination of the circovirus were determined based on the available circovirus genome sequences. The origin of circoviruses can be traced back to fish circovirus, which might derive from fish genome, and human contributes to transmission of fish circovirus to other species. Furthermore, mosquitos, ticks, bats, and/or rodents might play a role as intermediate hosts in circovirus intra- and inter-species transmission. Two major lineages (A and B) of circoviruses are identified, and frequent recombination events accelerate their variation and spread. The time to the most recent common ancestor of circoviruses can be traced back to around A.D. 600 and has been evolving at a rate of 10-4 substitutions site-1 year-1 for a long time.DiscussionThese comprehensive findings shed light on the evolutionary origin, population dynamics, transmission model, and genetic recombination of the circovirus providing valuable insights for the development of prevention and control strategies against circovirus infections.

Abstract Assistive powered wheelchairs will bring patients and elderly the ability of remain mobile without the direct intervention from caregivers. Vital signs from users can be collected and analyzed remotely to allow better disease prevention and proactive management of health and chronic conditions. This research proposes an autonomous wheelchair prototype system integrated with biophysical sensors based on Internet of Thing (IoT). A powered wheelchair system was developed with three biophysical sensors to collect, transmit and analysis users’ four vital signs to provide real-time feedback to users and clinicians. A user interface software embedded with the cloud artificial intelligence (AI) algorithms was developed for the data visualization and analysis. An improved data compression algorithm Minimalist, Adaptive and Streaming R-bit (O-MAS-R) was proposed to achieve a higher compression ratio with minimum 7.1%, maximum 45.25% compared with MAS algorithm during the data transmission. At the same time, the prototype wheelchair, accompanied with a smart-chair app, assimilates data from the onboard sensors and characteristics features within the surroundings in real-time to achieve the functions including obstruct laser scanning, autonomous localization, and point-to-point route planning and moving within a predefined area. In conclusion, the wheelchair prototype uses AI algorithms and navigation technology to help patients and elderly maintain their independent mobility and monitor their healthcare information in real-time.

Abstract The change of fracture propagation direction caused by stress interference between fractures is one of the main reasons that affect shale gas productivity. Natural fractures will be damaged by the induced stress, and the induced stress field produced by natural fracture damage will in turn affect the propagation of hydraulic fractures. Previous studies usually ignored the impact of stress field variation caused by natural fracture damage, leading to inaccurate fracture propagation simulation results. A new model for simulating hydraulic fracturing-induced stress field is established with consideration of the influence of natural fracture damage. Then, the natural fracture-induced stress is analyzed in open and closed fracture states. Through superposition of stress fields of natural fractures and hydraulic fractures, the interaction among open and closed natural fractures, reservoir and hydraulic fracture, and the corresponding fracture property evolution are studied. The results demonstrate that induced stress is not affected by elastic modulus and Poisson's ratio of the rock. The induced stress difference at the fracture tip is proportional to the net pressure and the length of hydraulic fractures. The results provide guidance for the optimal design of fracturing. When the deflection angle of hydraulic fracture is less than 90°, the maximum induced stress difference at the fracture tip decreases with the reduction in the deflection angle. When the deflection angle of hydraulic fracture is smaller than 90° or the deflection angle of natural fracture is smaller than 45°, the steering of hydraulic fracture is less hindered, which is beneficial to the formation of complex fracture network.

Abstract Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.

Abstract The NLRP3 inflammasome plays an important role in protecting the host from infection and aseptic inflammation, and its regulatory mechanism is not completely understood. Dysregulation of NLRP3 can cause diverse inflammatory diseases. HECTD3 is a E3 ubiquitin ligase of the HECT family that has been reported to participate in autoimmune and infectious diseases. However, the relationship between HECTD3 and the NLRP3 inflammasome has not been well studied. Herein, we show that HECTD3 blocks the interaction between NEK7 and NLRP3 to inhibit NLRP3 inflammasome assembly and activation. In BMDMs, Hectd3 deficiency promotes the assembly and activation of NLRP3 inflammasome and the secretion of IL-1β, while the overexpression of HECTD3 inhibits these processes. Unexpectedly, HECTD3 functions in an E3 activity independent manner. Mechanically, the DOC domain of HECTD3 interacts with NACHT/LRR domain of NLRP3, which blocks NLRP3-NEK7 interaction and NLRP3 oligomerization. Furthermore, HECTD3 inhibits monosodium urate crystals (MSU)-induced gouty arthritis, a NLRP3-related disease. Thus, we reveal a novel regulatory mechanism of NLRP3 by HECTD3 and suggest HECTD3 could be a potential therapeutic target for NLRP3-dependent pathologies.

Abstract Cultivated peanut (Arachis hypogaea L.) represents one of the most important oil and cash crops world-widely. Unlike many other legumes, peanuts absorb nitrogen through their underground pods. Despite this unique feature, the relationship between yield and nitrogen uptake within the pod zone remains poorly understood. In our pot experiment, we divided the underground peanut part into two zones—pod and root—and investigated the physiological and agronomic traits of two peanut cultivars, SH11 (large seeds, LS) and HY23 (small seeds, SS), at 10 (S1), 20 (S2), and 30 (S3) days after gynophores penetrated the soil, with nitrogen application in the pod zone. Results indicated that nitrogen application increased pod yield, kernel protein content, and nitrogen accumulation in plants. For both LS and SS peanut cultivars, optimal nitrogen content was 60 kg·hm− 2, leading to maximum yield. LS cultivar exhibited higher yield and nitrogen accumulation increases than SS cultivar. Nitrogen application up-regulated the expression of nitrogen metabolism-related genes in the pod, including nitrate reductase (NR), nitrite reductase (NIR), glutamine synthetase (GS), glutamate synthase (NADH-GOGAT), ATP binding cassette (ABC), and nitrate transporter (NRT2). Additionally, nitrogen application increased enzyme activity in the pod, including NR, GS, and GOGAT, consistent with gene expression levels. These nitrogen metabolism traits exhibited higher up-regulations in the large-seeded cultivar than in the small-seeded one and showed a significant correlation with yield in the large-seeded cultivar at S2 and S3. Our findings offer a scientific basis for the judicious application and efficient utilization of nitrogen fertilization in peanuts, laying the groundwork for further elucidating the molecular mechanisms of peanut nitrogen utilization.

This study aimed to determine the optimal dietary net energy concentration for the reproductive performance, immune function, milk composition, and gut microbiota of primiparous sows during lactation. Forty primiparous lactating sows (Landrace × Yorkshire) with similar body backfat thicknesses were randomly allocated into five treatment groups and fed diets with different dietary net energy concentrations of 10.05 MJ/kg, 10.47 MJ/kg, 10.89 MJ/kg, 11.30 MJ/kg, and 11.72 MJ/kg. The results showed that there were no differences in the performance of piglets, while there was a decrease in the daily feed intake of sows (p = 0.079, linear) as dietary net energy concentration increased. With the increasing dietary net energy concentration, the plasma insulin levels of sows increased (p < 0.01, linear), the plasma glucose levels tended to increase (p = 0.074, linear), and the blood urea nitrogen levels tended to decrease (p = 0.063, linear). Moreover, the plasma total superoxide dismutase activity of sows increased (p < 0.05, quadratic) and the plasma malondialdehyde content of sows decreased (p < 0.05, quadratic) by increasing the dietary net energy concentration. Interestingly, with the increase in dietary net energy concentration, the plasma immunoglobulin M content of sows increased, the milk immunoglobulin M, immunoglobulin G, immunoglobulin A and the percentage of milk fat increased (p < 0.05, linear), and the milk secretory immunoglobulin A content also increased (p < 0.05, linear and quadratic). The milk immunoglobulins and milk fat content of sows fed with net energy concentration of 11.72 MJ/kg were highest. Moreover, there were significant differences in the α-diversity, β-diversity, and relative abundance of gut microbiota in sows fed with different dietary net energy concentrations. At the phylum level, Spirochaetota and Bacteroidota in the gut microbiota of sows were mainly affected by increasing the dietary net energy concentration. Furthermore, the correlation analysis showed that milk immunoglobulin content had a significant negative correlation with the relative abundance of Bacteroidota, and plasma malondialdehyde content also had a significant negative correlation with the relative abundance of Spirochaetota. In summary, these results suggest that increasing the dietary net energy concentration to 11.72 MJ/kg can increase immunological substances in milk, improve milk quality, and alter the composition of gut microbiota in primiparous lactating sows.